Anti-inflammatory mediators

Discuss the pathophysiology of sepsis as it relates to endotoxin, peptidoglycan, and pro-and anti-inflammatory mediators. 

The key factor in the development of sepsis is inflammation. Inflammation is intended to be a local and contained response to infection or injury. Infection or injury is controlled through pro- and anti-inflammatory mediators. Pro-inflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue.1,13-16 In order to control the intensity and duration of the inflammatory response, antiinflammatory mediators are released that act to regulate pro-inflammatory mediators.15-16 The balance between pro- and anti-inflammatory mediators localizes infection/injury of host tissue.13-16 However, systemic responses ensue when equilibrium in the inflammatory process is lost. 

The inflammatory process in sepsis is linked to the coagulation system. Pro-inflammatory mediators maybe procoagulant and antifibrinolytic, whereas anti-inflammatory mediators may be fibrinolytic. A key factor in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Protein C levels are decreased in septic patients. 

It is well known that the response to a drug can differ between diseased and nondiseased individuals. For example, the expression of both pro- and anti-inflammatory mediators changes in many diseases and conditions such as rheumatic diseases, myocardial infarction, angina, aging, and obesity [21]. This may have an impact on toxicity and pharmacokinetics, and in particular, when the drug interacts with these mediators. In addition the pharmacokinetics of a drug can be affected by disease in general, a topic that is discussed later in this chapter. 

Bondeson J, FoxweU B, Brennan F, Feldmann M (1999) Defining therapeutic targets by using adenovirus blocking NF-kappaB inhibits both inflammatory and destructive mechanisms in rheumatoid synovium but spares anti-inflammatory mediators. Proc Natl Acad Sci USA 96 5668-5673... 

Sepsis involves activation of inflammatory pathways, and a complex interaction between proinflammatory and anti-inflammatory mediators plays a major role in the pathogenesis of sepsis. The key proinflammatory mediators include tumor necrosis factor-a (TNF-a), interleukin 1/3 (IL-1/3), and interleukin 6 (IL-6), which are released by activated macrophages. Other mediators that may be important for the pathogenesis of sepsis include interleukin 8 (IL-8), platelet-activating factor (PAF), leukotrienes, and thromboxane A2. " The significant anti-inflammatory mediators include IL-1 receptor antagonist (IL-lra), IL-4, and IL-10. These anti-inflammatory cytokines inhibit the production of the proinflammatory cytokines and down-regulate some inflammatory cells. 

FIGURE 117-2. The balance between pro- and anti-inflammatory mediators. 

Carter JM, Corson N, Driscoll KE et al (2006) A comparative dose-related response of several key pro- and anti-inflammatory mediators in the lungs of rats, mice, and hamsters after subchronic inhalation of carbon black. J Occup Environ Med 48 1265-1278 Cohen AJ, Anderson HR, Ostro B et al (2005) The global burden of diseases due to outdoor air pollution. J Toxicol Environ Health 68 1301-1307 Delfino RJ, Sioutas C, Malik S (2005) Potential role of ultrafine particles in associations between airborne particle mass and cardiovascular health. Environ Health Perspect 113 934—946 Delfino RJ, Staimer N, Gillen D et al (2006) Personal and ambient air pollution is associated with increased exhaled nitric oxide in children with asthma. Environ Health Perspect 114 1736-1743... 

Vachier, 1., P. Chanez et al. 2002. Endogenous anti-inflammatory mediators from arachidonate in human neutrophils. 290(1) 219-224. 

Musiek, E.S., J.D. Brooks, M. Joo, E. Brunoldi, A. Porta, G. Zanoni, G. Vidari et al. 2008. Electrophihc cyclopentenone neuroprostanes are anti-inflammatory mediators formed from the peroxidation of the omega-3 polyunsaturated fatty acid docosahexaenoic acid.. Journal of Biological Chemistry 283 19927-35. 

It is widely accepted that angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. This balance is conceptually very similar to that of the pro- and anti-inflammatory mediators that modulate an appropriate and specific inflammatory response [11]. 

In this aspect, novel anti-inflammatory mediators, including resolvins and protectins derived from docosahexaenoic acid (DHA, 22 6 FA), are discovered in association with the beneficial effects of dietary DHA on prevention of cardiovascular diseases [37, 38], In contrast, lipidomics research further confirmed the association of a variety of eicosanoids, oxylipins, and endocannabinoids with initiation and progression of cardiovascular diseases [39], These studies strongly suggest that the levels of n-3 and n-6 PUFA should be well balanced. 

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